Most patients develop chronic pancreatitis after prolonged ethanol abuse. It is generally believed that ethanol contributes to the evolution of pancreatitis by sensitizing the gland to injury by other potentially harmful factors, either genetic (e.g. CFTR mutations) or acquired (e.g. infectious agents, drugs of abuse, etc.), This relationship between ethanol abuse and chronic pancreatitis has complicated studies focusing on the mechanisms responsible for chronic pancreatitis and convinced most investigators that successful studies directed at elucidating the early events in clinical chronic pancreatitis will depend upon the development of good experimental models of the disease. Ideally, the disease in those models should resemble :he clinical disease morphologically and it should be dependent upon exposure to ethanol. Furthermore, it would be helpful if the model was elicited in mice since this would allow investigators to exploit the abundance of genetically altered mouse strains in mechanistic studies. To date, unfortunately, no such model has been developed. Rather, the models most frequently employed involve either (a) exposing ethanol fed rats to the combined effects of acute inflammation and administration of cyclosporine A (b) subjecting non-ethanol fed mice to repeated episodes of acute pancreatic inflammation or (c) exposing isolated pancreatic cells to pancreatitis-related agents under in-vitro conditions. We have recently obtained preliminary evidence that mice fed an ethanol-containing diet for six weeks and then subjected to repeated episodes of non-ethanol induced acute pancreatitis develop changes that are characteristic of chronic pancreatitis i.e. pancreatic fibrosis, and intra-pancreatic deposition of collagen. The current R21 proposal will build upon these preliminary observations by pursuing the following specific aims: (1) to determine, at the protein or enzyme activity level, if ethanol triggers a pro-fibrogenetic alteration in matrix remodeling enzymes; (2) to determine whether it is the exposure to ethanol alone, the repeated episodes of inflammation alone, or the combination of these two events that leads to pancreatic stellate cell activation and collagen synthesis during chronic pancreatitis; and (3) to demonstrate the utility of this model by using it, along with genetically modified mouse strains, in studies that examine the role of matrix-remodeling enzymes in the evolution of ethanol-dependent chronic pancreatitis.